Unwanted side effects such as central nervous system depression and risk of addiction limit the ability to manage acute and chronic pain states even if adequate pain relief has been achieved. Since pain can originate from the persistent activation of peripheral nociceptive neurons, the development of new therapies that can selectively block pain at the primary afferent nerve terminal would represent a novel and significant achievement in pain management. We have recently characterized a cDNA clone encoding a vanilloid (capsaicin) receptor expressed in peripheral sensory neurons that transduce pain (Nature 389: 816-824, 1997). This cDNA termed, "vanilloid receptor type-1", (VR1) encodes an ion channel which confers several important properties relevant to peripheral pain transduction. It is activated by a class of compounds such as capsaicin, which are painful if topically applied to humans but following repeated application, produce analgesia, VR-1 is also activated by intense heat in the range that is associated with the sensation of burning pain and is potentiated under conditions of low pH as exists with disorders of inflammation and infection. We will test the hypothesis that vanilloid receptors arise from a common gene by characterizing genomic clones encoding vanilloid receptors. In the preliminary results, we demonstrate an additional subtype cDNA (termed VR-2). Therefore, by expressing VR-2 in Xenopus oocytes, we will test the hypothesis that VR-2 encodes a vanilloid receptor with responses to noxious chemical and heat stimuli that are distinct from VR-1 and that VR-2 is differentially expressed in nociceptive neurons by in situ hybridization and quantitate those difference by RT-PCR. Since capsaicin is used as topical analgesics to treat pain, characterization of vanilloid receptor subtypes should provide important insight into the advancement of therapies designed to selectively block pain.